1. Field of the Invention
Compounds of this invention are analogues of natural prostaglandins.
Natural prostaglandins are twenty-carbon atom alicyclic compounds related to prostanoic acid which has the following structure: ##STR2## By convention, the carbon atoms of I are numbered sequentially from the carboxylic carbon atom. An important sterochemical feature of I is the trans-orientation of the side-chains C.sub.1 -C.sub.7 and C.sub.13 -C.sub.20. All natural prostaglandins have this orientation. In I, as elsewhere in this specification, a dashed line ( ) indicates projection of a covalent bond below a reference plane, such as those formed by the cyclopentyl ring or the bonds of a carbon atom (alpha-configuration), while a wedged line ( ) represents direction above that plane (beta-configuration). Those conventions apply to all compounds subsequently discussed in this specification.
In one system of nomenclature suggested by N. A. Nelson in J. Med Chem., 17: 911 (1972), prostaglandins are named as derivatives or modifications of the natural prostaglandins. In a second system, the I.U.P.A.C. (International Union of Pure and Applied Chemistry) system of nomenclature, prostaglandins are named as substituted heptanoic acids. A third system of nomenclature (also described by Nelson), names all prostaglandins as derivatives or modifications of prostanoic acid (structure I) or prostane (the hydrocarbon equivalent of structure I). The latter system is used by Chemical Abstracts.
Natural prostaglandins have the general structure, ##STR3## in which L and M may be ethylene or cis-vinylene radicals five-membered ring ##STR4##
Prostaglandins are classified according to the functional groups present in the five-membered ring and the presence of double bonds in the ring or chains. Prostaglandins of the A-class (PGA or prostaglandin A) are characterized by an oxo group at C.sub.9 and a double bond at C.sub.10 -C.sub.11 (.DELTA..sup.10,11); those of the B-class (PGB) have an oxo group at C.sub.9 and a double bond at C.sub.8 -C.sub.12 (.DELTA..sup.8,12); compounds of the C-class (PGC) contain an oxo group at C.sub.9 and a double bond at C.sub.11 -C.sub.12 (.DELTA..sup.11,12); members of the D-class (PGD) have an oxo group at C.sub.11 and an alpha-oriented hydroxy group at C.sub.9 ; prostaglandins of the E-class (PGE) have an oxo group at C.sub.9 and an alpha-oriented hydroxyl group at C.sub.11 ; and members of the F.sub..alpha. -class (PGF.sub..alpha.) have an alpha-directed hydroxyl group at C.sub.9 and an alpha-oriented hydroxyl group at C.sub.11. Within each of the A, B, C, D, E, and F classes of prostaglandins are three subclassifications based upon the presence of double bonds in the side-chains at C.sub.5 -C.sub.6, C.sub.15 -C.sub.14, or C.sub.17 -C.sub.18. The presence of a trans-unsaturated bond only at C.sub.13 -C.sub.14 is indicated by the subscript numeral 1; thus, for example, PGE.sub.1 (or prostaglandin E.sub.1) denotes a prostaglandin of the E-type (oxo-group at C.sub.9 and an alpha-hydroxyl at C.sub.11) with a trans-double bond at C.sub.13 -C.sub.14. The presence of both a trans-double bond at C.sub.13 -C.sub.14 and a cis-double bond at C.sub.5 -C.sub.6 is denoted by the subscript numeral 2; for example, PGE.sub.2. Lastly, a trans-double bond at C.sub.13 -C.sub.14, a cis-double bond at C.sub.5 -C.sub.6 and a cis-double bond at C.sub.17 -C.sub.18 is indicated by the subscript numeral 3; for example, PGE.sub.3. The above notations apply to prostaglandins of the A, B, C, D, and F series as well; however, in the last, the alpha-orientation of the hydroxyl group at C.sub.9 is indicated by the subscript Greek letter .alpha. after the numerical subscript.
The three systems of nomenclature as they apply to natural PGE.sub.3.alpha. are shown below: ##STR5## Nelson system:- Prostaglandin F.sub.3.alpha. or PGF.sub.3.alpha. (shortened form);
I.U.P.A.C. system: 7[3R,5S-Dihydroxy-2S-(3S-hydroxy-1E, 5Z-octadienyl)-cyclopent-1R-yl]-5Z-heptenoic acid; and, Chemical Abstracts system: (5Z,9.alpha.,11.alpha., 13E,15S,17Z)-9,11,15-trihydroxyprosta-5,13,17-trien-1-oic acid.
It is important to note that in all natural prostaglandins there is an alpha-oriented hydroxyl group at C.sub.15. In the Cahn-Ingold-Prelog system of defining stereochemistry, that C.sub.15 hydroxyl group is in the S-configuration. The Cahn-Ingold-Prelog system is used to define stereochemistry of any asymmetric center outside of the carbocyclic ring in all three systems of nomenclature described above. This is in contrast to some prostaglandin literature in which the .alpha., .beta. designations are used, even at C.sub.15.
Various derivatives and analogues of the prostaglandins described above may be synthesized. Although these derivatives do not occur as such in nature, many of them possess activity related to their parent compounds. Such synthetic derivatives and analogues include the following:
A. 11-deoxy Derivatives of PGE and PGF Molecules
Formula II represents 11-deoxy PGE and PGF compounds when ##STR6## respectively.
In that formula, and others of this patent specification, a swung dash or serpentine line ( ) denotes a covalent bond which can be either in the alpha-configuration (projecting below the appropriate reference plane) or in the beta-configuration (projecting above the reference plane).
B. pgf.sub..beta. molecules.
Formula II represents PGF.sub..beta. compounds when ##STR7## C. 9-Deoxy Derivatives of PGE.
When ##STR8## in Formula II, the formula gives the 9-deoxy derivatives of PGE.
D. 9-deoxy-.DELTA..sup.9,10 Derivatives of PGE.
Formula II represents the 9-deoxy-.DELTA..sup.9,10 PGE compounds when ##STR9## E. 9a-Homo- and 9a-Homo-11-Deoxy Derivative of PGE and PGF Molecules.
These compounds are given by Formula II when ##STR10## represents, respectively, the 9a-homo-PGE, the 9a-homo-11-deoxy-PGE, the 9a-homo-PGF and the 9-a-homo-11-deoxy-PGF compounds.
F. 11a-Homo- Derivatives of PGE, PGF and PGA Molecules.
Replacement of ##STR11## in formula II represents the continued molecules. In particular, ##STR12## represent the 11a-homo-derivatives of, respectively, PGE, PGF and PGA.
G. 11-epi-PGE and PGF Molecules.
Formula II represents the 11-epi-compounds of PGE and PGF respectively, when ##STR13## H. 8-Iso-, 12-Iso or 8,12-Bis-Iso-(Ent)-Prostaglandins.
The 8-Iso-, 12-iso- or 8,12-bis-iso-(ent) compounds are obtained from Formula II by replacing: ##STR14## The iso modifications of Formula II may be divided into all of the sub-classes with varying ring oxygenation as described above.
Recent research indicates that prostaglandins appear ubiquitously in animal tissues. They, as well as many of their synthetic analogues, have important biochemical and physiological effects in a variety of mammalian systems.
In the endocrine system, for example, experimental evidence indicates prostaglandins influence the hormone synthesis or release of hormones in the secretory glands. In rats, PGE.sub.1 and PGE.sub.2 increase the release of the growth hormone while PGA.sub.1 increases its synthesis. In sheep, PGE.sub.1 and PGF.sub.1.alpha. inhibit ovarian progesterone secretion. In a variety of mammals, PGF.sub.1.alpha. and PGF.sub.2.alpha. act as luteolytic factors. In mice, PGE.sub.1, PGE.sub.2, and PGF.sub.1.alpha. and PGF.sub.1.beta. increase thyroid activity. In hypophysectomized rats, PGE.sub.1, PGE.sub.2 and PGF.sub.1.alpha. stimulate stereoidogenesis in the adrenal glands.
In the mammalian male reproductive system, PGE.sub.1 contracts the smooth muscle of the vas deferens. In the female reproductive system, PGE and PGF.sub..alpha. compounds contract uterine smooth muscle. In general, PGE, PGB and PGA compounds relax in vitro human uterine muscle strips, while those of the PGF.sub..alpha. class contact such isolated preparations. PGE compounds, in general, promote fertility in the female reproductive system while PGF.sub.2.alpha. has contragestational effects. PGF.sub.2.alpha. also appears to be involved in the mechanism of menstruation. In general, PGE.sub.2 produces potent oxytocic effects in inducing labor, while PGF.sub.2.alpha. induces spontaneous abortions in early pregnancy.
PGF.sub..alpha. and PGE compounds have been isolated from a variety of nervous tissue and they seem to act as neurotransmitters. PGE.sub.1 retards whereas PGF.sub.2.alpha. facilitates transmission along motor pathways in the central nervous system. PGE.sub.1 and PGE.sub.2 reportedly inhibit transmitter release from adrenergic nerve endings in the guinea pig.
Prostaglandins stimulate contraction of gastrointestinal smooth muscle in vivo and in vitro. In dogs, PGA.sub.1, PGE.sub.1, and PGE.sub.2 inhibit gastric secretion. PGA.sub.1 exhibits similar activity in man.
In most mammalian respiratory tracts, PGE and PGF compounds effect in vitro preparations of tracheal smooth muscle. Specifically, PGE.sub.1 and PGE.sub.2 relax, while PGF.sub.2.alpha. contracts, the smooth muscle. The human lung normally contains PGE and PGF compounds; consequently, some cases of bronchial asthma may involve an imbalance in the production or metabolism of those compounds.
Prostaglandins are involved in certain hematic mechanisms in mammals. PGE.sub.1, for example, inhibits thrombogenesis in vitro through its effects in blood platelets.
In a variety of mammalian cardiovascular systems, compounds of the PGE and PGA classes are vasodilators whereas those of the PGF.sub..alpha. class are vasoconstrictors, by virtue of their action on vascular smooth muscle.
Prostaglandins naturally appear in the kidney and reverse experimental and clinical renoprival hypertension.
The prostaglandins and their analogues have broad clinical implications. In obstetrics and gynecology, they may find use in fertility control, treatment of menstrual disorders, the induction of labor, and the correction of hormone disorders. In gastroenterology, they may help treat peptic ulcers and various disorders involving motility, secretion, and absorption in the gastrointestinal tract. They may, in the respiratory area, prove beneficial in the therapy of bronchial asthma and other diseases involving bronchoconstriction. In hematology, they may display utility as anti-clotting agents in diseases such as venous thrombosis, thrombotic coronary occlusion and other diseases involving thrombi. For circulatory diseases, they have therapeutic utility in hypertension, peripheral vasopathies and cardiac disorders.
The following references include a more complete review of the chemical, physiological and pharmacological aspects of the prostaglandins: The Prostaglandins, Vol. I., P. Ramwell, Ed., New York, Plenum Press, 1973; Ann. N.Y. Acad. Sci., 180: 1-568 (1971); Higgins and Braunwald, J. Am. Med. Assn., 53: 92-112 (1972); Osterling, Marozowich, and Roseman, J. Phar. Sci., 61: 1861-1895 (1972); and Nakano, Resident and Staff Phys., 19: 92, 94-99, and 102-106 (1973).